Objective:To
estimate frequency of acute bacterial meningitis (ABM) in early
childhood in hospital admissions, to describe clinical and diagnostic
features, and to analyze mortality, complications and long term sequelae.
Design: Prospective study. Setting: Pediatric wards and
Rehabilitation Center of KEM Hospital, Pune. Method: Study
subjects between the ages of 1 months to 5 years with ABM were
recruited. Clinical details were recorded. CSF was analysed by routine
biochemical methods, antigen detection tests (Latex agglutination LAT)
and microbiological studies on special media. Management was as per
standard protocols. Survivors were followed up long term with
neurodevelopmental studies and rehabilitation programmes. Results:
In a study period of 2 years, 54 children (1.5% of all admissions)
satisfied the criteria of ABM in early childhood; 78% were below one
year and 52% were under the age of six months. Chief presentation was
high fever, refusal of feeds, altered sensorium and seizures. Meningeal
signs were present in only 26%. CSF C-reactive protein was positive in
41%, gram stain was positive in 67%, LAT in 78% and cultures grew
causative organisms in 50% of the cases. The final etiological diagnosis
(as per LAT and/or cultures) were Streptococcus pneumoniae 39%,
Hemophilus influenzae type b 26% and others in 35%. The others included
one case of Neisseria meningitidis and 10 who were LAT negative and
culture sterile. 39% patients developed acute neurological complications
during the hospital course. 31% children with ABM died in hospital or at
home soon after discharge. Six were lost to follow up. Of the 31
children, available for long term follow up (1-3 years), 14 (45%) had no
sequelae. The remaining had significant neurodevelopmental handicaps
ranging from isolated hearing loss to severe mental retardation with
multiple disabilities. Conclusion: ABM in early childhood has a
considerable mortality, morbidity and serious long term sequelae.
Neurodevelopmental follow up and therapy should begin early. Etiological
diagnosis can be enhanced by LAT and good culture media. H. influenzae b
and S. pneumoniae account for more than 60% of ABM in early childhood.

Key words:Acute
bacterial meningitis, Long term Sequelae.

ACUTE bacterial
meningitis (ABM) is an important disease of early childhood, with high
case fatality and risk of neurologic handicaps(1). The community
incidence of ABM in India is not known. The exact etiological diagnosis
is often not possible, because of poor culture facilities(2,3). The
three organisms commonly associated with ABM in early childhood in
western countries are Hemophilus influenzae type b, S. Pneumoniae and
Neisseria meningitidis. However, the etiology may vary in
different parts of the world(1). Many of these infections are likely to
be preventable in the near future(4,5).

We have prospectively
examined the hospital based frequency of ABM in early childhood,
especially in relation to its etiology. The clinical and diagnostic
features, mortality, complications and especially long term sequelae
were also analysed.

Subjects and Methods

The study was conducted
in the Pediatric Department of KEM Hospital, Pune, which includes a 6
bedded Pediatric Intensive Care Unit (PICU) and a 40 bedded General
Pediatric ward. All patients admitted with a clinical diagnosis of ABM
during April 1997 to March 1999 were included if they satisfied the
following criteria: (i) age between 1 month and 5 years; (ii)
cerebrospinal fluid (CSF) showing protein>40 mg/dl, sugar <40
mg/dl and >10 neutrophils/hpf. Other investigations included complete
blood counts, chest x-ray, renal and liver function tests, electrolytes
and blood culture. C-reactive protein (CRP) was determined in the CSF
and categorized as positive or negative. CSF antigen detection by latex
agglutination (LAT) was done using Slidex Meningite kit 5 (Biomerieux,
France) for the detection of soluble antigens of H. influenzae
type b, S. pneumoniae and N. meningitidis groups A, B and
C(6,7).

Ultrasound and CT scan of
the head were carried out whenever required.

Management

Following diagnosis, the
patients were treated with antibiotics based on their age: (i)
patients between 1 and 6 months’ old: cefotaxime with gentamicin or
amikacin; (ii) >6 months’ old: ampicillin or penicillin with
chloramphenicol, or cefotaxime or ceftriaxone. Intravenous dexamethasone
was given in a dose of 0.15 mg/kg/dose every 6 hr for four days (the
first dose given with or prior to the first dose of antibiotics).
Antibiotics were changed (if required) as per the sensitivity results
and clinical response. Appropriate supportive care including attention
to fluids, electrolytes, ventilation, parenteral nutrition and
neurosurgical intervention was provided.

Children who recovered
were regularly followed up in the out-patients clinic and the Pediatric
Rehabilitation Center. Home visits were arranged for patients who did
not come for regular follow up. Evaluations on follow up included
detailed neurological examination, audiometry, BERA and tests for
intelligence and development quotients.

The study was approved by
the Ethics Committee of the hospital and informed consent of the parents
was obtained.

Results

Of 3686 admissions, 54
children (1.5%) (age 1 month to 5 years) had ABM; 28 (54.9%) were males.
Forty two patients were below the age of one year and 28 (51.9% of all
cases) under the age of six months. Only 2 of the 54 children with ABM
had been immunized with H. influenzae vaccine.

The presenting features
included high fever (96%), altered sensorium (98%), refusal of feeds
(83%) and convulsions (81%); two children had circulatory failure.
Meningeal signs were elicited in 26% only. Twenty one patients (39%) had
received antibiotics for 1-3 days prior to admission. The CSF was turbid
in majority of cases (85%); CSF proteins ranged from 40-660 mg/dl, sugar
from 8-72 mg/dl, and leukocytes from 40-10,000/cu mm. Majority of the
leukocytes were neutrophils; 10 children (19%) showed 10 to 30%
lymphocytes. CRP was positive in the CSF in 22 patients (41%), gram
stain was postive in 36 cases (67%), but correlated with culture or
positive LAT in 29 cases only (54%).

CSF cultures were
positive in 27 (50%) and LAT was positive in 36 (67%). The etiology of
ABM, on basis of CSF culture and LAT showed S. pneumoniae in 21
(39%) and H. influenzaetype b in 14 (26%). Only one
patient showed infection with N. meningitidis. The LAT was
positive in all patients with positive CSF cultures for the above
organisms.

Of the 18 patients (33%)
who had a negative LAT, 8 were culture positive for other organisms (Pseudomonas,
Staphylo-coccus and betahemolytic streptococci in 2 each and Streptococcus
pyogenes and Citrobacter in 1 each). An etiologic diagnosis
was not made in 10 (19%) patients.

Blood cultures were
positive in 4 (H.influenzae, alpha-hemolytic strepto-coccus,
Pseudomonas and S.aureus in one each). Positive blood
culture, CSF culture and positive LAT was present only in one patient
with H. influenzae infection. Patients with positive blood
cultures for Pseudomonas and S. aureus had sterile CSF
cultures.

The clinical and
laboratory features of the three major groups of ABM are seen in Table
I. There were no significant differences between the S.
pneumoniae and H. influenzae groups at admission, except
higher CSF cells in the latter (P = 0.01). Most cultures of S.
pneumoniae and H. influenzae were sensitive to standard
medications. Streptococci were resistant to cefotaxime,
penicillin and ampicillin in 2 cases. Two patients with H. influenzae
infection showed resistance to ampicillin and vancomycin.

During the course of
treatment, antibiotics were changed as per protocol in 10 children (the
added or changed drugs included vancomycin in 2, piperacillin and
ceftazidime in 2 each, ceftriaxone in 4, tobramycin in 1 and
chloramphenicol in 3).

Complications seen during
hospitalization were subdural effusion (n=10), hemiplegia (n = 4),
ventricular abscesses and hydrocephalus (n = 2), cerebral infarcts (n =
6), cranial nerve palsy (n = 3) and isolated hydrocephalus in one
patient; 5 patients had more than one complication. The subdural
effusions were treated conservatively. Both patients with ventricular
abscesses required frequent tapping (one requiring craniotomy) and later
developed hydrocephalus. Two of the 4 patients with hemiplegia showed no
focal deficit at recovery.

Table I-Clinical and Laboratory Features of Acute Bacterial Meningitis

Eighteen (41%) of 44
children with seizures continued to have fits beyond four days of
admission; of these 6 patients died, while 10 showed persistent
seizures. Of the 26 children who had seizures restricted to first four
days of admission, 8 died, 16 improved (with no convulsions) and 2 had
persistent seizures.

Outcome

Of the 54 patients with
ABM, 10 (19%) died in hospital within 1-7 days of admission (6 died
within 48 hr of admission) and 5 were discharged against medical advice
in a critical condition (3 of these died at home soon after discharge
while two were lost to follow up). The others were discharged after 6 to
45 days (mean 12 days). Four patients died at home, 2 each due to
complications and 2 of unrelated causes. Six patients could not be
traced for further follow up.

31 patients therefore,
were available for long term follow up. Of these, 14 (45%) had a good
outcome with no neurological sequelae. In others, sequelae ranged from
isolated hearing loss to severe developmental delay with a combination
of motor, hearing and visual defects (Table II). Twelve children
had persistent seizures. On analysis of immediate complications with
long term outcome of the 10 patients with subdural effusion, 5 had no
sequelae, one had isolated hearing loss, 3 had moderate to severe
developmental delay and 1 died. Two of the 6 children with cerebral
infarcts died, one had isolated hearing loss and 3 had moderate to
severe developmental delay with multiple disabilities. Of the 2 children
with cerebral abscess one died and the other was left with multiple
handicaps and hydrocephalus. Patients with pneumococcal meningitis had
higher mortality, risk of complication and neurological sequelae
compared to H. influenzae infection (P = 0.04, Fischer exact
test).

Discussion

ABM accounted for 1.5% of
all our pediatric admissions during the study period. We restricted our
study to the age group of 1 month to 5 years to focus on the distinct
clinical group excluding neonatal meningitis and meningitis in older
children. Kabra, et al. reviewing a survey of pyogenic meningitis
in major centers in India reported a frequency of 0.5 to 2.6% of
hospital admissions(2). The community prevalence in international
studies have been quoted between 3/100,000 in USA(9), 16/100,000 in
UK(10) to 45.8/100,000 in Brazil(9). Though all these numbers are
relatively small, the importance of ABM is chiefly because of the
associated high mortality and serious morbidity.

In our study, of a total
of 54 cases, 17 (31.5%) died in hospital or soon after discharge. The
case fatality rate in India and other developing countries has been
quoted as 16 to 30%(1,3,11-13). Approximately one-third of all deaths in
our study occurred in the first 48 hr of hospitalization, reflecting the
critical condition of the patients at admission. Even in developed
countries, inspite of availability of all facilities, the case fatality
rates of bacterial meningitis in early childhood approaches 10%(9).

The complication rate in
ABM too, is high inspite of aggressive management(3,9,14). Atleast 40%
of our patients had acute complications, including subdural effusions,
cerebral infarcts, ventricular abscesses, hydrocephalus, cranial nerve
palsies, repeated seizures and motor deficits. Even more disturbing than
the high mortality (and complications) were the long term sequelae and
disabling handicaps in the survivors. On follow up, only one-fourth of
the children tested were neurodevelopmentally normal. A significant
proportion were left with hearing deficits and moderate to severe mental
retardation with multiple disabilities causing considerable financial
and emotional burden to the family. Early and careful follow up with
neurodevelopmental and auditory testing is important because more than
half of these disabled children appeared normal at hospital discharge.
Similar long term sequelae of ABM have been described from both
developing(14-16) and developed countries(17-18), though such data from
India is lacking.

Early diagnosis, prompt
initiation of therapy and supportive care are important for improving
the long term outcome(2,9,11). Unfortunately, as seen in the present
study, signs of meningitis cannot be used for making an early diagnosis.
Altered sensorium and convulsions are late features. Hence a high index
of suspicion is necessary to suspect meningitis and perform a lumbar
puncture. A presumptive diagnosis of ABM is usually possible on the
basis of biochemical analysis of CSF. Difficulties arise if patients are
already treated with antibiotics as CSF may show normal sugar content
and cells may be predominantly lymphocytes. In such cases, one has to
rely on other CSF parameters and clinical clues. Unfortunately what
seems to be difficult especially in our country is accurate
bacteriological diagnosis of meningitis(2,3,19). Gram-staining, though a
cheap and easy technique, can identify organisms at best in 60% of
cases(3,11,20), whereas CSF culture results are positive in not more
than 15-35% patients(2,3,19). The culture results can perhaps be
improved with the use of special media and special techniques especially
for H. influenzae as in the present study. However, most western
series quote a culture positivity of upto 90%(9). The reasons for low
yields of cultures in our country are not clear but may include poor
quality of culture media and use of antibiotics prior to
hospitalization(3,6). Other quick and sensitive techniques of diagnosis
of ABM obviously need to be urgently explored. Of great promise is the
CSF latex agglutination test (LAT) which various authors have confirmed
as simple with superior sensitivity and specificity and unaffected by
previous antibiotics therapy(6,7,11). In the present study, more than
two-third patients were positive for LAT whereas cultures were positive
in only one-half. However the LAT kits are expensive and available only
for common organisms and hence not suitable as the lone diagnostic
technique in ABM. Besides, the kits cannot provide information on
antibiotics sensitivity and hence both techniques (LAT and culture
sensitivity) should be used together. In our series, 10 patients were
negative on culture and LAT, but the final diagnosis was made on CSF
biochemistry and clinical features. In such cases, it is difficult to
rule out tuberculous and viral meningitis in the initial stages.

Until recently the
commonest organism associated with ABM in early childhood was H.
influenzae(9). However, most Indian studies have quoted a low
isolates of the organism(2,3,19). Whether this is because the organism
is difficult to grow or whether the incidence is genuinely low is not
clear. In our earlier studies, we have shown a high susceptibility of
infants to infection with H. influenzae(4). In the present study,
the contribution by various organisms was H. influenzaetype b
in 26%, S. pneumoniae in 39% and N. meningitidis in
2%. The low incidence of infection with N. meningitidis and
relatively high incidence of pneumococcal infection has been
noted by other Indian workers(3,17).

Table II-Outcome in Acute Bacterial Meningitis

Outcome

All
54

Hemophilus
14

S. pneumoniae
21

others
19

Died

17(31.5)

3 (21.4)

7 (33.3)

7 (36.8)

Complications

21 (38.9)*

Subdural effusion

10

5

4

1

Hemiparesis

4

0

3

1

Hydrocephalus

3

-

1

2

Infarcts

6

1

3

2

Ventricular abscess

2

-

-

2

Cranial nerve palsy

3

-

2

1

Lost to follow up

6

0

4

2

Long term follow up in 31 patients

No sequelae

14 (45.2)

7

2

5

Persistent seizures

12

2

7

3

Isolated hearing loss

4

3

0

1

Hemiparesis

2

0

1

1

Mild to moderate MR

2

-

1

1

Moderate to severe
developmental delay

9

1

6

2

Figures in parenthesis indicate percentage. * More than 1 complication in 5 children

The management of ABM
includes a suitable combination of antibiotics, dexamethasone for first
few days, and importantly, intensive care therapy especially for shock
and raised intracranial pressure(2,5,9). Treatment of complications
includes antiepileptic drugs and neurosurgical procedures.
Rehabilitation programmes are necessary for the handicapped. All these
add to the tremendous financial and emotional burden on the family.
Measures to prevent ABM are thus extemely important.

The vaccine against H.
influenzae has reduced infection with one of the most important
causes of ABM in advanced countries. This is now being introduced as an
optional vaccine in India. However, to be effective against H.
influenzae meningitis it should be given early in infancy as
majority of cases of ABM occur in the first six months of life.
Theoretically, pneumococcal meningitis too is a vaccine preventable
disease, but unfortunately, the currently available polysaccharide
vaccine is not effective in children under two years of age(5,9).
Universal use of meningococcal vaccine is unattractive as the disease is
generally sporadic and vaccine is of limited immunogenicity(9). However
if H. influenzae and pneumococcal vaccines become a reality, the
incidence of ABM in early childhood can reduce by more than 60%, with
considerable reduction in the financial and emotional cost burden of the
disease.

Acknowledgement

Special thanks are due to
Dr. Bhavana Doshi and Ms. Manjusha Rajarshi, Consultants, Aventis
Pasteur, Mumbai for their help in the study.

Contributors:
NC and SwB were involved in clinical data collection. MM and KBN carried
out the bacteriological investigations. ShB co-ordinated the study,
drafted the paper and will act as guarantor. AB co-ordinated the study
and analysed the data. AP supervised the study and reviewed the
manuscript. DL prepared the study design and AD monitored data
collection.

Funding: Aventis
Pasteur, France.

Competing interests:
None stated.

Key
Messages

• Good culture media and antigen detection
tests may be used to improve bacteriological diagnosis of
pyogenic meningitis.